The goal of the project is to diminish the morbidity and mortality associated with esophageal cancer as patients with this cancer continue to suffer from extremely poor survival and high case-fatality rates. Esophageal adenocarcinoma (EAC) is the most common histologic type of esophageal malignancy in the US and has experienced an alarmingly rapid and largely unexplained rise in incidence over the past four decades in much of the western world. Previous attempts to curb the morbidity and mortality associated with EAC in the US have focused on an endoscopic screening, which is invasive and costly. However, innovative new technologies for esophageal cancer screening that are both less invasive and costly have created the opportunity to lower the bar for screening to where it could be a realistic option, particularly for those who are higher risk. While the performance metrics of the device are important, equally critical are identifying and resolving barriers to implementation. We propose to study potential factors for patients, providers and health care systems that could impede screening programs. This R01 proposal will leverage a previously developed and validated natural history simulation model of EAC. The PI has made significant contributions to the fields of esophageal cancer screening, prevention and treatment utilizing the EAC model to assess and analyze critical aspects of EAC cancer control. The prior work and model will provide an exceptionally strong foundation for the current research project. The research team is comprised of experienced investigators who provide the broad and complementary expertise necessary for this project and have a track record of successful collaboration. The overarching premise of our proposal is that novel approaches to esophageal cancer screening have the potential to improve EAC mortality, but that the successful implementation and population impact will depend on: 1) the screening modality characteristics; 2) patient, provider, and health system?s barriers; and 3) the profile of the patients to be screened. We will accomplish these project goals by completing four specific aims. In Aim 1 we will use our validated simulation model of esophageal cancer to test and assess whether a cell sampling device can be cost-effective for population screening. In Aim 2 we will study potential patient, provider and health system barriers to esophageal cancer screening. For Aim 3 we will personalize screening by determining which patient profiles will benefit from screening. Finally, in Aim 4 will assess the population cancer control impact of the potential implementation of the esophageal cancer screening strategy defined by the prior aims. By award period end, we will have developed a personalized approach to targeted EAC screening that is rational and cost-effective.